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Invisible Brain Injury and the Origin of Intraventricular Hemorrhage in Premature Infants

Brain injury in very low birthweight babies is extremely common: 1 in 10 survivors have cerebral palsy, and up to 50% have cognitive deficits. Unfortunately, the pathogenesis of brain injury in this population remains poorly understood. This is largely because we can’t image acute injury to developing neurons with ultrasound or MRI: the acute injury is “invisible”. We can only see the sequelae of neuronal injury such as bleeding and late chronic volume loss, and damage to the white matter. This contrasts with injury to mature neurons, which rapidly swell after injury, producing a clear signal on diffusion-weighted imaging (DWI) MRI. We hypothesize that, as a consequence of their unique membrane salt and water transport, immature neurons shrink in response to injury. Neuronal shrinkage requires new imaging strategies for clinical detection. Further, widespread shrinkage would strain and potentially tear local blood vessels. This is a new candidate mechanism of intraventricular hemorrhage, which is a common brain injury in premature infants. To test our hypotheses, we will measure the volume of immature neurons during and after acute injury, and correlate the volume changes with the expression of membrane salt and water transporters. We will further test this relationship by measuring the extracellular volume change, which forms the basis for diffusion weighted MRI imaging, as well as total tissue volume change. We will monitor volume responses using multiphoton imaging, ion-sensitive fluorescence lifetime imaging (FLIM), and super resolution shadow imaging (SUSHI) in vitro and in vivo. We will use transgenic intracellular Cl-sensitive fluorophores, as well as novel fluorophores that we have conjugated to dextran so that Cl detection is restricted to the extracellular space. We then can use this information to develop new techniques to detect acute brain injury, and to prevent neuronal shrinkage and intraventricular hemorrhage in premature infants.